Imidazo-fused heterocycles and uses thereof

ABSTRACT

Compounds and methods in the fields of chemistry and medicine are disclosed. Some of the disclosed embodiments include compounds, compositions and methods of using imidazole-fused heterocycle amines. Some of the disclosed embodiments include imidazo-fused heterocycle compounds useful to treat leukemia and other hematopoietic disorders.

INCORPORATION BY REFERENCE TO PRIORITY APPLICATION

The present application is a division of U.S. application Ser. No.15/070,718, filed Mar. 15, 2016 and to be issued as U.S. Pat. No.10,807,983, which claims the benefit of priority to U.S. Appl. No.62/133,935, filed Mar. 16, 2015, each of which is incorporated byreference in its entirety.

FIELD

Compounds and methods in the fields of chemistry and medicine aredisclosed. Some of the disclosed embodiments include compounds,compositions and methods of using imidazo-fused heterocycles. Some ofthe disclosed embodiments include imidazo-fused heterocycles useful totreat hematological malignancy.

BACKGROUND

Fms-like tyrosine kinase 3 (Flt3), also termed as fatal liver kinase-2(Flt2) is a cytokine receptor whose signaling is part of the normaldevelopment of hematopoietic stem cells and progenitor cells. Flt3 is aproto-oncogene and its mutation can lead to certain types of leukemia.Internal tandem duplications of Flt3 (Flt3-ITD) are the most commonmutations associated with acute myelogenous leukemia (AML), oftenassociated with a poor prognosis, and has been considered as atherapeutic target (See C. C. Smith, et al. Nature 485: 260-263 (2012)).

Flt3 inhibitors have been developed in different stages of clinicaltrials for treatment of AML patients with Flt3-ITD mutations.Quizartinib is a small molecule selective class III tyrosine kinaseinhibitor including Flt-3 (see C. Qi, et al. J Med Chem 52(23): 7808-16(2009)). In clinical studies, quizartinib has shown a high rate ofresponse as monotherapy in relapsed/refractory Flt3-ITD positivepatients, although quizartinib-resistance mutantions can be developed.There is a need for next generation Flt3 inhibitors that are moreselective and less likely to develop resistance.

SUMMARY

Compounds, compositions and methods of using heterocycle amines aredisclosed. Some of the disclosed embodiments include imidazo-fusedhetereoaryls useful to treat hematopoietic disorders.

Some embodiments described herein are directed to a compound of FormulaI:

-   -   or a salt, ester, amide, or prodrug thereof,    -   wherein X is selected from N or CR^(4a); X′ is selected from N        or CR^(4b); Y is selected from N or CR^(5a); Y′ is selected from        N or CR^(5b); provided at least one of X, X′, Y, and Y′ is N;    -   R¹ is selected from the group consisting of hydrogen, halogen,        —OR⁶, —CN, —NR⁷R⁸, —CH₂OR⁶, —CH₂NR⁷R⁸, an optionally substituted        C₁₋₆ alkyl, an optionally substituted C₁₋₆ haloalkyl, an        optionally substituted C₂₋₆ alkenyl, an optionally substituted        C₂₋₆ alkynyl, an optionally substituted (5 to 7 membered        heterocyclyl)alkyl, an optionally substituted 5 to 7 membered        heterocyclyl, an optionally substituted aralkyl; an optionally        substituted (5 or 6 membered heteroaryl)alkyl, an optionally        substituted C₁₋₆ heteroalkyl, —C(═O)R⁶, —C(═O)OR⁶, —C(═O)NR⁷R⁸,        —NHC(═O)R⁶, —SO₂R⁶, and —SO₂NR⁷R⁸;    -   each of R², R³, R^(4a) and R^(4b) is independently selected from        the group consisting of hydrogen, halogen, C₁₋₆ alkyl, OH, and        C₁₋₆ alkoxy;    -   each of R^(5a) and R^(5b) is independently selected from the        group consisting of hydrogen, halogen, —OR⁶, —CN, —NR⁷R⁸,        —CH₂OR⁶, an optionally substituted aryl, an optionally        substituted 5 to 10 membered heteroaryl, an optionally        substituted 5-10 membered heterocyclyl, an optionally        substituted C₃₋₇ carbocyclyl, an optionally substituted C₁₋₆        alkyl, an optionally substituted C₁₋₆ haloalkyl, an optionally        substituted C₁₋₆ heteroalkyl, —C(═O)R⁶, —C(═O)OR⁶, —C(═O)NR⁷R⁸,        —NHC(═O)R⁶, —SO₂R⁶, and —SO₂NR⁷R⁸;    -   each R⁶ is independently selected from hydrogen, an optionally        substituted C₁₋₁₀ alkyl, an optionally substituted C₁₋₁₀        haloalkyl, or an optionally substituted C₁₋₆ heteroalkyl; and    -   each R⁷ and R⁸ is independently selected from hydrogen; an        optionally substituted C₁₋₁₀ alkyl; an optionally substituted        C₁₋₁₀ haloalkyl; or an optionally substituted C₁₋₆ heteroalkyl;        or R⁷ and R⁸ are joined together with the nitrogen atom to which        they are attached to form an optionally substituted C₃₋₇        cycloalkyl or 3 to 7 membered heterocyclyl ring.

In some embodiments, the the compound of Formula (I) is also representedby Formula (II):

In some embodiments, the the compound of Formula (I) is also representedby Formula (III):

Some embodiments described herein are directed to pharmaceuticalcompositions comprising a compound of Formula (I), (II) or (III) asdescribed herein, or a pharmaceutically acceptable salt, ester, amide,or prodrug thereof, and a pharmaceutically acceptable carrier, diluent,excipient or combinations thereof.

Some embodiments described herein are directed to methods of treating adisorder responsive to inhibition of Flt3-mediated signal transductioncomprising administering to a subject in need thereof an effectiveamount of a compound of Formula (I), (II) or (III) as described herein,or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof,or a pharmaceutical composition thereof.

Some embodiments described herein are directed to methods of treating ahematopoietic disorder comprising administering to a subject in needthereof an effective amount of a compound of Formula (I), (II) or (III)as described herein, or a pharmaceutically acceptable salt, ester,amide, or prodrug thereof, or a pharmaceutical composition thereof. Insome embodiments, the hematopoietic disorder is selected from the groupconsisting of certain forms of leukemia, for example, acute myelogenousleukemia (AML).

DETAILED DESCRIPTION

Compounds and methods in the fields of chemistry and medicine aredisclosed. Some of the disclosed embodiments include compounds,compositions and methods of using heterocycle amines. Some of thedisclosed embodiments include heterocycle amines useful to treathematopoietic disorders.

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art. All patents, applications, published applications and otherpublications referenced herein are incorporated by reference in theirentirety unless stated otherwise. In the event that there are aplurality of definitions for a term herein, those in this sectionprevail unless stated otherwise. As used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. Unlessotherwise indicated, conventional methods of mass spectroscopy, NMR,HPLC, protein chemistry, biochemistry, recombinant DNA techniques andpharmacology are employed. The use of “or” or “and” means “and/or”unless stated otherwise. Furthermore, use of the term “including” aswell as other forms, such as “include”, “includes,” and “included,” isnot limiting. As used in this specification, whether in a transitionalphrase or in the body of the claim, the terms “comprise(s)” and“comprising” are to be interpreted as having an open-ended meaning. Thatis, the terms are to be interpreted synonymously with the phrases“having at least” or “including at least.” When used in the context of aprocess, the term “comprising” means that the process includes at leastthe recited steps, but may include additional steps. When used in thecontext of a compound, composition, or device, the term “comprising”means that the compound, composition, or device includes at least therecited features or components, but may also include additional featuresor components.

Unless specific definitions are provided, the nomenclatures utilized inconnection with, and the laboratory procedures and techniques of,analytical chemistry, synthetic organic chemistry, and medicinal andpharmaceutical chemistry described herein are those known in the art.Standard chemical symbols are used interchangeably with the full namesrepresented by such symbols. Thus, for example, the terms “hydrogen” and“H” are understood to have identical meaning. Standard techniques may beused for chemical syntheses, chemical analyses, pharmaceuticalpreparation, formulation, and delivery, and treatment of patients.Standard techniques may be used for recombinant DNA, oligonucleotidesynthesis, and tissue culture and transformation (e.g., electroporation,lipofection). Reactions and purification techniques may be performede.g., using kits according to manufacturer's specifications or ascommonly accomplished in the art or as described herein. The foregoingtechniques and procedures may be generally performed according toconventional methods well known in the art and as described in variousgeneral and more specific references that are cited and discussedthroughout the present specification. See e.g., Sambrook et al.Molecular Cloning: A Laboratory Manual (2d ed., Cold Spring HarborLaboratory Press, Cold Spring Harbor, N.Y. (1989)), which isincorporated herein by reference in its entirety for any purpose.

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter described.

“Solvate” refers to the compound formed by the interaction of a solventand a compound described herein or salt thereof. Suitable solvates arepharmaceutically acceptable solvates including hydrates.

The term “pharmaceutically acceptable salt” refers to salts that retainthe biological effectiveness and properties of a compound and, which arenot biologically or otherwise undesirable for use in a pharmaceutical.In many cases, the compounds disclosed herein are capable of formingacid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto. Pharmaceutically acceptableacid addition salts can be formed with inorganic acids and organicacids. Inorganic acids from which salts can be derived include, forexample, hydrochloric acid, hydrobromic acid, sulfuric acid, nitricacid, phosphoric acid, and the like. Organic acids from which salts canbe derived include, for example, acetic acid, propionic acid, glycolicacid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinicacid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamicacid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceuticallyacceptable base addition salts can be formed with inorganic and organicbases. Inorganic bases from which salts can be derived include, forexample, sodium, potassium, lithium, ammonium, calcium, magnesium, iron,zinc, copper, manganese, aluminum, and the like; particularly preferredare the ammonium, potassium, sodium, calcium and magnesium salts.Organic bases from which salts can be derived include, for example,primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, basic ionexchange resins, and the like, specifically such as isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine, andethanolamine. Many such salts are known in the art, as described in WO87/05297, Johnston et al., published Sep. 11, 1987 (incorporated byreference herein in its entirety).

As used herein, “C_(a) to C_(b)” or “C_(a-b)” in which “a” and “b” areintegers refer to the number of carbon atoms in the specified group.That is, the group can contain from “a” to “b”, inclusive, carbon atoms.Thus, for example, a “C₁ to C₄ alkyl” or “C₁₋₄ alkyl” group refers toall alkyl groups having from 1 to 4 carbons, that is, CH₃—, CH₃CH₂—,CH₃CH₂CH₂—, (CH₃)₂CH—, CH₃CH₂CH₂CH₂—, CH₃CH₂CH(CH₃)— and (CH₃)₃C—.

The term “halogen” or “halo,” as used herein, means any one of theradio-stable atoms of column 7 of the Periodic Table of the Elements,e.g., fluorine, chlorine, bromine, or iodine, with fluorine and chlorinebeing preferred.

As used herein, “alkyl” refers to a straight or branched hydrocarbonchain that is fully saturated (i.e., contains no double or triplebonds). The alkyl group may have 1 to 20 carbon atoms (whenever itappears herein, a numerical range such as “1 to 20” refers to eachinteger in the given range; e.g., “1 to 20 carbon atoms” means that thealkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbonatoms, etc., up to and including 20 carbon atoms, although the presentdefinition also covers the occurrence of the term “alkyl” where nonumerical range is designated). The alkyl group may also be a mediumsize alkyl having 1 to 9 carbon atoms. The alkyl group could also be alower alkyl having 1 to 4 carbon atoms. The alkyl group may bedesignated as “C₁₋₄ alkyl” or similar designations. By way of exampleonly, “C₁₋₄ alkyl” indicates that there are one to four carbon atoms inthe alkyl chain, i.e., the alkyl chain is selected from the groupconsisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl,sec-butyl, and t-butyl. Typical alkyl groups include, but are in no waylimited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiarybutyl, pentyl, hexyl, and the like.

As used herein, “alkoxy” refers to the formula —OR^(a) wherein R^(a) isan alkyl as is defined above, such as “C₁₋₉ alkoxy”, including but notlimited to methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy),n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy, and the like. Theterm “straight-chain alkoxy” refers to a group comprising the formula:—(CH₂)_(p)O— wherein p is any integer. Straight-chain alkoxy does notinclude substituted or branched alkoxy groups.

As used herein, “alkenyl” refers to a straight or branched hydrocarbonchain containing one or more double bonds. The alkenyl group may have 2to 20 carbon atoms, although the present definition also covers theoccurrence of the term “alkenyl” where no numerical range is designated.The alkenyl group may also be a medium size alkenyl having 2 to 9 carbonatoms. The alkenyl group could also be a lower alkenyl having 2 to 4carbon atoms. The alkenyl group may be designated as “C₂₋₄ alkenyl” orsimilar designations. By way of example only, “C₂₋₄ alkenyl” indicatesthat there are two to four carbon atoms in the alkenyl chain, i.e., thealkenyl chain is selected from the group consisting of ethenyl,propen-1-yl, propen-2-yl, propen-3-yl, buten-1-yl, buten-2-yl,buten-3-yl, buten-4-yl, 1-methyl-propen-1-yl, 2-methyl-propen-1-yl,1-ethyl-ethen-1-yl, 2-methyl-propen-3-yl, buta-1,3-dienyl,buta-1,2,-dienyl, and buta-1,2-dien-4-yl. Typical alkenyl groupsinclude, but are in no way limited to, ethenyl, propenyl, butenyl,pentenyl, and hexenyl, and the like.

As used herein, “alkynyl” refers to a straight or branched hydrocarbonchain containing one or more triple bonds. The alkynyl group may have 2to 20 carbon atoms, although the present definition also covers theoccurrence of the term “alkynyl” where no numerical range is designated.The alkynyl group may also be a medium size alkynyl having 2 to 9 carbonatoms. The alkynyl group could also be a lower alkynyl having 2 to 4carbon atoms. The alkynyl group may be designated as “C₂₋₄ alkynyl” orsimilar designations. By way of example only, “C₂₋₄ alkynyl” indicatesthat there are two to four carbon atoms in the alkynyl chain, i.e., thealkynyl chain is selected from the group consisting of ethynyl,propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-3-yl, butyn-4-yl, and2-butynyl. Typical alkynyl groups include, but are in no way limited to,ethynyl, propynyl, butynyl, pentynyl, and hexynyl, and the like.

The term “haloalkyl” refers to an alkyl in which at least one hydrogenatom is replaced with a halogen atom. In certain of the embodiments inwhich two or more hydrogen atoms are replaced with halogen atoms, thehalogen atoms are all the same as one another. In certain of suchembodiments, the halogen atoms are not all the same as one another.

As used herein, “heteroalkyl” refers to a straight or branchedhydrocarbon chain containing one or more heteroatoms, that is, anelement other than carbon, including but not limited to, nitrogen,oxygen and sulfur. The heteroalkyl group may have 1 to 20 carbon atom,although the present definition also covers the occurrence of the term“heteroalkyl” where no numerical range is designated. The heteroalkylgroup may be designated as “C₁₋₄ heteroalkyl” or similar designations.By way of example only, “C₁₋₄ heteroalkyl” indicates that there are oneto four carbon atoms in the heteroalkyl chain and additionally one ormore heteroatoms. In some embodiments, the term “heteroalkyl” refers toan alkyl group comprising two or more carbon atoms in which at least one—CH₂— unit of the alkyl group is replaced with a substituent selectedfrom —C═O, —NH—, —S— or —O—; or at least one

unit is replaced with

Examples of heteroalkyls include, but are not limited to, CH₃C(═O)CH₂—,CH₃C(═O)CH₂CH₂—, CH₃CH₂C(═O)CH₂CH₂—, CH₃C(═O)CH₂CH₂CH₂—, CH₃NHC(═O)CH₂—,CH₃C(═O)NHCH₂—, CH₃OCH₂CH₂—, CH₃NHCH₂—, and the like.

The term “aromatic” refers to a ring or ring system having a conjugatedpi electron system and includes both carbocyclic aromatic (e.g., phenyl)and heterocyclic aromatic groups (e.g., pyridine). The term includesmonocyclic or fused-ring polycyclic (i.e., rings which share adjacentpairs of atoms) groups provided that the entire ring system is aromatic.

As used herein, the term “carbocycle” or “carbocyclyl” refers tonon-aromatic cyclic ring or ring system containing only carbon atoms inthe ring system backbone. Carbocylic rings may be formed by three, four,five, six, seven, eight, nine, or more than nine carbon atoms. Thecarbocyclyl group may have 3 to 20 carbon atoms, although the presentdefinition also covers the occurrence of the term “carbocyclyl” where nonumerical range is designated. The carbocyclyl group may also be amedium size carbocyclyl having 3 to 10 carbon atoms. The carbocyclylgroup could also be a carbocyclyl having 3 to 6 carbon atoms. Thecarbocyclyl group may be designated as “C₃₋₆ carbocyclyl” or similardesignations. Examples of carbocyclyl rings include, but are not limitedto, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl,2,3-dihydro-indene, bicycle[2.2.2]octanyl, adamantyl, andspiro[4.4]nonanyl.

As used herein, “cycloalkyl” means a fully saturated carbocyclyl ring orring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl.

A “(carbocyclyl)alkyl” is a carbocyclyl group connected, as asubstituent, via an alkylene group, such as “C₄₋₁₀ (carbocyclyl)alkyl”and the like, including but not limited to, cyclopropylmethyl,cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl,cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl,cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, and the like. Insome cases, the alkylene group is a lower alkylene group.

As used herein, “aryl” refers to an aromatic ring or ring system (i.e.,two or more fused rings that share two adjacent carbon atoms) containingonly carbon in the ring backbone. When the aryl is a ring system, everyring in the system is aromatic. The aryl group may have 6 to 18 carbonatoms, although the present definition also covers the occurrence of theterm “aryl” where no numerical range is designated. In some embodiments,the aryl group has 6 to 10 carbon atoms. The aryl group may bedesignated as “C₆₋₁₀ aryl,” “C₆ or C₁₀ aryl,” or similar designations.Examples of aryl groups include, but are not limited to, phenyl,naphthyl, azulenyl, and anthracenyl.

An “aralkyl” or “arylalkyl” is an aryl group connected, as asubstituent, via an alkylene group, such as “C₇₋₁₄ aralkyl” and thelike, including but not limited to benzyl, 2-phenylethyl,3-phenylpropyl, and naphthylalkyl. In some cases, the alkylene group isa lower alkylene group (i.e., a C₁₋₄ alkylene group).

As used herein, “heteroaryl” refers to an aromatic ring or ring system(i.e., two or more fused rings that share two adjacent atoms) thatcontain(s) one or more heteroatoms, that is, an element other thancarbon, including but not limited to, nitrogen, oxygen and sulfur, inthe ring backbone. When the heteroaryl is a ring system, every ring inthe system is aromatic. The heteroaryl group may have 5-18 ring members(i.e., the number of atoms making up the ring backbone, including carbonatoms and heteroatoms), although the present definition also covers theoccurrence of the term “heteroaryl” where no numerical range isdesignated. In some embodiments, the heteroaryl group has 5 to 10 ringmembers or 5 to 7 ring members. The heteroaryl group may be designatedas “5-7 membered heteroaryl,” “5-10 membered heteroaryl,” or similardesignations. Examples of heteroaryl rings include, but are not limitedto, furyl, thienyl, phthalazinyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl,thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,quinolinyl, isoquinlinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl,indolyl, isoindolyl, and benzothienyl.

A “heteroaralkyl” or “heteroarylalkyl” is heteroaryl group connected, asa substituent, via an alkylene group. Examples include but are notlimited to 2-thienylmethyl, 3-thienylmethyl, furylmethyl, thienylethyl,pyrrolylalkyl, pyridylalkyl, isoxazollylalkyl, and imidazolylalkyl. Insome cases, the alkylene group is a lower alkylene group (i.e., a C₁₋₄alkylene group).

The term “heterocycle” or “heterocyclyl” means a non-aromatic cyclicring or ring system containing at least one heteroatom in the ringbackbone. Heterocyclyls may be joined together in a fused, bridged orspiro-connected fashion. Heterocyclyls may have any degree of saturationprovided that at least one ring in the ring system is not aromatic. Theheteroatom(s) may be present in either a non-aromatic or aromatic ringin the ring system. The heterocyclyl group may have 3 to 20 ring members(i.e., the number of atoms making up the ring backbone, including carbonatoms and heteroatoms), although the present definition also covers theoccurrence of the term “heterocyclyl” where no numerical range isdesignated. The heterocyclyl group may also be a medium sizeheterocyclyl having 3 to 10 ring members. The heterocyclyl group couldalso be a heterocyclyl having 3 to 6 ring members. The heterocyclylgroup may be designated as “3-6 membered heterocyclyl” or similardesignations. In preferred six membered monocyclic heterocyclyls, theheteroatom(s) are selected from one up to three of O, N or S, and inpreferred five membered monocyclic heterocyclyls, the heteroatom(s) areselected from one or two heteroatoms selected from O, N, or S. Examplesof heterocyclyl rings include, but are not limited to, azepinyl,acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl,imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl,piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl,pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl,1,3-dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-oxathianyl,1,4-oxathiinyl, 1,4-oxathianyl, 2H-1,2-oxazinyl, trioxanyl,hexahydro-1,3,5-triazinyl, 1,3-dioxolyl, 1,3-dioxolanyl, 1,3-dithiolyl,1,3-dithiolanyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl,oxazolidinonyl, thiazolinyl, thiazolidinyl, 1,3-oxathiolanyl, indolinyl,isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl,tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro-1,4-thiazinyl,thiamorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl, andtetrahydroquinoline. Examples of heterocycles include, but are notlimited to the following:

-   -   wherein D, E, F, and G independently represent a heteroatom.        Each of D, E, F, and G may be the same or different from one        another.

A “(heterocyclyl)alkyl” is a heterocyclyl group connected, as asubstituent, via an alkylene group. Examples include, but are notlimited to, imidazolinylmethyl and indolinylethyl.

The term “heteroatom” refers to an atom other than carbon or hydrogen.Heteroatoms, typically, are independently selected from oxygen, sulfur,nitrogen, and phosphorus, but heteroatoms are not limited to thoseatoms. In embodiments in which two or more heteroatoms are present, thetwo or more heteroatoms may all be the same as one another, or some orall of the two or more heteroatoms may each be different from theothers.

The substituent “R” appearing by itself and without a number designationrefers to a substituent selected from hydrogen, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, and 5-10 membered heterocyclyl, as defined herein.

Each of the substituent “R_(A)” and “R_(B)” appearing by itself andwithout a number designation refers to a substituent independentlyselected from hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇carbocyclyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, and 5-10 memberedheterocyclyl, as defined herein.

The term “O-carboxy” refers to the group consisting of formula RC(═O)O—.

The term “C-carboxy” refers to the group consisting of formula —C(═O)OR.

As used herein, “acyl” refers to —C(═O)R, wherein R is hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.Non-limiting examples include formyl, acetyl, propanoyl, benzoyl, andacryl.

The term “acetyl” refers to the group consisting of formula —C(═O)CH₃.

The term “trihalomethanesulfonyl” refers to the group consisting offormula X₃CS(═O)₂— where X is a halogen.

The term “cyano” refers to the group consisting of formula —CN.

The term “cyanato” refers to the group consisting of formula —OCN.

The term “isocyanato” refers to the group consisting of formula —NCO.

The term “thiocyanato” refers to the group consisting of formula —CNS.

The term “isothiocyanato” refers to the group consisting of formula—NCS.

The term “sulfinyl” refers to the group consisting of formula —S(═O)—R.

The term “sulfonyl” refers to the group consisting of formula —S(O)₂R.

The term “S-sulfonamido” refers to the group consisting of formula—S(═O)₂NR_(A)R_(B).

The term “N-sulfonamido” refers to the group consisting of formulaR_(A)S(═O)₂NR_(B)—.

The term “O-carbamyl” refers to the group consisting of formula—OC(═O)—NR_(A)R_(B).

The term “N-carbamyl” refers to the group consisting of formulaR_(B)OC(═O)N(R_(A))—.

The term “O-thiocarbamyl” refers to the group consisting of formula—OC(═S)—NR_(A)R_(B).

The term “N-thiocarbamyl” refers to the group consisting of formulaR_(B)OC(═S)N(R_(A))—.

The term “C-amido” refers to the group consisting of formula—C(═O)—NR_(A)R_(B).

The term “N-amido” refers to the group consisting of formulaR_(B)C(═O)N(R_(A))—.

The term “oxo” refers to the group consisting of formula ═O.

The term “carbonyl” refers to the group consisting of formula —C(═O)—.

The term “thiocarbonyl” refers to the group consisting of formula—C(═S)—.

The term “ester” refers to a chemical moiety with formula —COOR, where Ris selected from hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇carbocyclyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, and 5-10 memberedheterocyclyl, as defined herein.

An “amino” group refers to a “—NR_(A)R_(B)” group in which R_(A) andR_(B) are each independently selected from hydrogen, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, and 5-10 membered heterocyclyl, as defined herein. Anon-limiting example includes free amino (i.e., —NH₂).

An “aminoalkyl” group refers to an amino group connected via an alkylenegroup.

An “alkoxyalkyl” group refers to an alkoxy group connected via analkylene group, such as a “C₂₋₈ alkoxyalkyl” and the like.

An “O-carboxy” group refers to a “—OC(═O)R” group in which R is selectedfrom hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, asdefined herein.

A “C-carboxy” group refers to a “—C(═O)OR” group in which R is selectedfrom hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, asdefined herein. A non-limiting example includes carboxyl (i.e.,—C(═O)OH).

As used herein, a substituted group is derived from the unsubstitutedparent group in which there has been an exchange of one or more hydrogenatoms for another atom or group. Unless otherwise indicated, when agroup is deemed to be “substituted,” it is meant that the group issubstituted with one or more substituents independently selected fromC₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, C₁-C₆ heteroalkyl, C₃-C₇carbocyclyl (optionally substituted with halo, C₁-C₆ alkyl, C₁-C₆alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy),C₃-C₇-carbocyclyl-C₁-C₆-alkyl (optionally substituted with halo, C₁-C₆alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), 5-10membered heterocyclyl (optionally substituted with halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), 5-10 memberedheterocyclyl-C₁-C₆-alkyl (optionally substituted with halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), aryl (optionallysubstituted with halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, andC₁-C₆ haloalkoxy), aryl(C₁-C₆)alkyl (optionally substituted with halo,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), 5-10membered heteroaryl (optionally substituted with halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), 5-10 memberedheteroaryl(C₁-C₆)alkyl (optionally substituted with halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), halo, cyano,hydroxy, C₁-C₆ alkoxy, C₁-C₆ alkoxy(C₁-C₆)alkyl (i.e., ether), aryloxy,sulfhydryl (mercapto), halo(C₁-C₆)alkyl (e.g., —CF₃), halo(C₁-C₆)alkoxy(e.g., —OCF₃), C₁-C₆ alkylthio, arylthio, amino, amino(C₁-C₆)alkyl,nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido,N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, acyl,cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl,and oxo (═O). Wherever a group is described as “optionally substituted”that group can be substituted with the above substituents.

It is to be understood that certain radical naming conventions caninclude either a mono-radical or a di-radical, depending on the context.For example, where a substituent requires two points of attachment tothe rest of the molecule, it is understood that the substituent is adi-radical. For example, a substituent identified as alkyl that requirestwo points of attachment includes di-radicals such as —CH₂—, —CH₂CH₂—,—CH₂CH(CH₃)CH₂—, and the like. Other radical naming conventions clearlyindicate that the radical is a di-radical such as “alkylene” or“alkenylene.”

The term “pharmaceutically acceptable carrier” or “pharmaceuticallyacceptable excipient” as used herein, means one or more compatible solidor liquid filler diluents or encapsulating substances, which aresuitable for administration to a mammal. The term “compatible”, as usedherein, means that the components of the composition are capable ofbeing commingled with the subject compound, and with each other, in amanner such that there is no interaction, which would substantiallyreduce the pharmaceutical efficacy of the composition under ordinary usesituations. Pharmaceutically-acceptable carriers must, of course, be ofsufficiently high purity and sufficiently low toxicity to render themsuitable for administration preferably to an animal, preferably mammalbeing treated.

The term “pharmaceutical agent” refers to a chemical compound orcomposition capable of inducing a desired therapeutic effect in apatient. In certain embodiments, a pharmaceutical agent comprises anactive agent, which is the agent that induces the desired therapeuticeffect. In certain embodiments, a pharmaceutical agent comprises aprodrug. In certain embodiments, a pharmaceutical agent comprisesinactive ingredients such as carriers, excipients, and the like.

The term “therapeutically effective amount” as used herein, refer to anamount of a compound sufficient to cure, ameliorate, slow progressionof, prevent, or reduce the likelihood of onset of the identified diseaseor condition, or to exhibit a detectable therapeutic, prophylactic, orinhibitory effect. The effect can be detected by, for example, theassays disclosed in the following examples. The precise effective amountfor a subject will depend upon the subject's body weight, size, andhealth; the nature and extent of the condition; and the therapeutic orcombination of therapeutics selected for administration. Therapeuticallyand prophylactically effective amounts for a given situation can bedetermined by routine experimentation that is within the skill andjudgment of the clinician.

The term “prodrug” refers to a pharmaceutical agent that is convertedfrom a less active form into a corresponding more active form in vivo.

Isotopes may be present in the compounds described. Each chemicalelement as represented in a compound structure may include any isotopeof said element. For example, in a compound structure a hydrogen atommay be explicitly disclosed or understood to be present in the compound.At any position of the compound that a hydrogen atom may be present, thehydrogen atom can be any isotope of hydrogen, including but not limitedto hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, referenceherein to a compound encompasses all potential isotopic forms unless thecontext clearly dictates otherwise.

Where the compounds disclosed herein have at least one chiral center,they may exist as individual enantiomers and diastereomers or asmixtures of such isomers, including racemates. Separation of theindividual isomers or selective synthesis of the individual isomers isaccomplished by application of various methods which are well known topractitioners in the art. Unless otherwise indicated, all such isomersand mixtures thereof are included in the scope of the compoundsdisclosed herein. Furthermore, compounds disclosed herein may exist inone or more crystalline or amorphous forms. Unless otherwise indicated,all such forms are included in the scope of the compounds disclosedherein including any polymorphic forms. In addition, some of thecompounds disclosed herein may form solvates with water (i.e., hydrates)or common organic solvents. Unless otherwise indicated, such solvatesare included in the scope of the compounds disclosed herein.

The term “pharmaceutically acceptable” refers to a formulation of acompound that does not significantly abrogate the biological activity, apharmacological activity and/or other properties of the compound whenthe formulated compound is administered to a patient. In certainembodiments, a pharmaceutically acceptable formulation does not causesignificant irritation to a patient.

The term “co-administer” refers to administering more than onepharmaceutical agent to a patient. In certain embodiments,co-administered pharmaceutical agents are administered together in asingle dosage unit. In certain embodiments, co-administeredpharmaceutical agents are administered separately. In certainembodiments, co-administered pharmaceutical agents are administered atthe same time. In certain embodiments, co-administered pharmaceuticalagents are administered at different times.

The term “patient” includes human and animal subjects.

The term “substantially pure” means an object species (e.g., compound)is the predominant species present (i.e., on a molar basis it is moreabundant than any other individual species in the composition). Incertain embodiments, a substantially purified fraction is a compositionwherein the object species comprises at least about 50 percent (on amolar basis) of all species present. In certain embodiments, asubstantially pure composition will comprise more than about 80%, 85%,90%, 95%, or 99% of all species present in the composition. In certainembodiments, the object species is purified to essential homogeneity(contaminant species cannot be detected in the composition byconventional detection methods) wherein the composition consistsessentially of a single species.

Compounds

Some embodiments disclosed herein relate to a compound of formula (I) asdescribed above or a pharmaceutically acceptable salt thereof.

In some embodiments, X is N, X′ is CR^(4b), Y is CR^(5a), and Y′ isCR^(5b). In some such embodiments, R^(4b) is hydrogen. In some suchembodiments, R^(5a) is hydrogen. In some such embodiments, R^(5b) ishydrogen.

In some embodiments, X′ is N, X is CR^(4a), Y is CR^(5a), and Y′ isCR^(5b). In some such embodiments, R^(4a) is hydrogen. In some suchembodiments, R^(5a) is hydrogen. In some such embodiments, R^(5b) ishydrogen.

In some embodiments, Y is N, X is CR^(4a), X′ is CR^(4b), and Y′ isCR^(5b). In some such embodiments, R^(4a) is hydrogen. In some suchembodiments, R^(4b) is hydrogen. In some such embodiments, R^(5b) ishydrogen.

In some embodiments, Y is N, X is CR^(4a), X′ is CR^(4b), and Y isCR^(5a). In some such embodiments, R^(4a) is hydrogen. In some suchembodiments, R^(4b) is hydrogen. In some such embodiments, R^(5a) ishydrogen.

In some embodiments, the compound of Formula (I) is also represented byFormula (II):

In some such embodiments, each R^(4a) and R^(4b) is hydrogen.

In some embodiments, the compound of Formula (I) is also represented byFormula (III):

In some such embodiments, each R^(4a) and R^(5a) is hydrogen.

In some embodiments, R¹ is an optionally substituted (5 to 7 memberedheterocyclyl)alkyl. In some such embodiments, R¹ is an optionallysubstituted (5 membered heterocyclyl)alkyl. In some such embodiments, R¹is pyrrolidyl-CH₂—. In one embodiment, R¹ is 1-pyrrolidinyl-CH₂—. Insome embodiments, R¹ is an optionally substituted (6 memberedheterocyclyl)alkyl. In some such embodiments, R¹ is selected frompiperidinyl-CH₂— or morpholine-CH₂—. In one embodiment, R¹ is1-piperidinyl-CH₂—. In another embodiment, R¹ is 1-morpholino-CH₂—. Insome embodiments, R¹ is an optionally substituted 5 to 7 memberedheterocyclyl. In some sucy embodiments, R¹ is an optionally substituted6 membered heterocyclyl. In some such embodiments, R¹ is selected fromoptionally substituted morpholinyl, optionally substituted piperazinyl,or optionally substituted piperidinyl. In one embodiment, R¹ is1-morpholinyl. In another embodiment, R¹ is4-substituted-piperazin-1-yl. In yet another embodiment, R¹ is and1-substituted-piperidin-4-yl.

In some embodiments, R² is hydrogen. In some embodiments, R³ ishydrogen. In some further embodiments, both R² and R³ are hydrogen.

In some embodiments, R^(5a) is hydrogen and R^(5b) is selected from CNor an optionally substituted 5 to 10 membered heteroaryl. In some suchembodiments, R^(5b) is an optionally substituted 6 membered heteroaryl.In some such embodiments, R^(5b) is selected from pyridyl, pyrimidyl,pyrazinyl, or pyridazinyl. In some other embodiments, R^(5b) is anoptionally substituted 5 membered heteroaryl. In one such embodiment,R^(5b) is pyrazolyl.

In some embodiments, the compound of formula (I) is selected from

or pharmaceutically acceptable salts, esters, amides, or prodrugsthereof.Exemplary Synthetic Methods

In certain embodiments, compounds of the present invention can bysynthesized using the following Schemes.

Scheme I describes general synthesis of the2-(2-pyridinylamino)imidazo[1,2-a]pyrazines or2-(2-pyridinylamino)imidazo[1,2-a]pyridazines of structure 6. Anaminopyridazine of structure 1 is treated sequentially with TsCl and2-bromoacetamide in the presence of bases to afford an intermediate ostructure 2. Treatment of the intermediate of structure 2 withtrifluoroacetic acid generates a bicyclic compound of structure 3.Palladium catalyzed coupling of structure 3 with a boronic acid affordsa compound of structure 4. Deprotection of the trifluoroacetyl groupfollowed by treatment of a 2-chloropyridine compound of structure 5yield the final product of structure 6.

One of skill in the art will recognize that analogous synthetic schemesmay be used to synthesize similar compounds. One of skill will recognizethat compounds of the present invention may be synthesized using othersynthesis schemes. In certain embodiments, the invention provides a saltcorresponding to any of the compounds provided herein.

Certain Pharmaceutical Compositions

Some embodiments include pharmaceutical compositions comprising: (a) asafe and therapeutically effective amount of a compound described herein(including enantiomers, diastereoisomers, tautomers, polymorphs, andsolvates thereof), or pharmaceutically acceptable salts thereof; and (b)a pharmaceutically acceptable carrier, diluent, excipient or combinationthereof.

The compounds useful as described above can be formulated intopharmaceutical compositions for use in treatment of these conditions.Standard pharmaceutical formulation techniques are used, such as thosedisclosed in Remington's The Science and Practice of Pharmacy, 21st Ed.,Lippincott Williams & Wilkins (2005), incorporated by reference in itsentirety.

In certain embodiments, a pharmaceutical composition comprising one ormore compounds of the present embodiments is prepared using knowntechniques, including, but not limited to mixing, dissolving,granulating, dragee-making, levigating, emulsifying, encapsulating,entrapping or tabletting processes.

In certain embodiments, a pharmaceutical composition comprising one ormore compounds of the present embodiments is a liquid (e.g., asuspension, elixir and/or solution). In certain of such embodiments, aliquid pharmaceutical composition comprising one or more compounds ofthe present embodiments is prepared using ingredients known in the art,including, but not limited to, water, glycols, oils, alcohols, flavoringagents, preservatives, and coloring agents.

In certain embodiments, a pharmaceutical composition comprising one ormore compounds of the present embodiments is a solid (e.g., a powder,tablet, and/or capsule). In certain of such embodiments, a solidpharmaceutical composition comprising one or more compounds of thepresent embodiments is prepared using ingredients known in the art,including, but not limited to, starches, sugars, diluents, granulatingagents, lubricants, binders, and disintegrating agents.

In certain embodiments, a pharmaceutical composition comprising one ormore compounds of the present embodiments is formulated as a depotpreparation. Certain such depot preparations are typically longer actingthan non-depot preparations. In certain embodiments, such preparationsare administered by implantation (for example subcutaneously orintramuscularly) or by intramuscular injection. In certain embodiments,depot preparations are prepared using suitable polymeric or hydrophobicmaterials (for example an emulsion in an acceptable oil) or ion exchangeresins, or as sparingly soluble derivatives, for example, as a sparinglysoluble salt.

In certain embodiments, a pharmaceutical composition comprising one ormore compounds of the present embodiments comprises a delivery system.Examples of delivery systems include, but are not limited to, liposomesand emulsions. Certain delivery systems are useful for preparing certainpharmaceutical compositions including those comprising hydrophobiccompounds. In certain embodiments, certain organic solvents such asdimethylsulfoxide are used.

In certain embodiments, a pharmaceutical composition comprising one ormore compounds of the present embodiments comprises a sustained-releasesystem. A non-limiting example of such a sustained-release system is asemi-permeable matrix of solid hydrophobic polymers. In certainembodiments, sustained-release systems may, depending on their chemicalnature, release compounds over a period of hours, days, weeks or months.

Certain compounds used in the pharmaceutical composition of the presentembodiments may be provided as pharmaceutically acceptable salts withpharmaceutically compatible counterions. Pharmaceutically compatiblesalts may be formed with many acids, including but not limited tohydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc.

In certain embodiments, a pharmaceutical composition comprising one ormore compounds of the present embodiments comprises an active ingredientin a therapeutically effective amount. In certain embodiments, thetherapeutically effective amount is sufficient to prevent, alleviate orameliorate symptoms of a disease or to prolong the survival of thesubject being treated. Determination of a therapeutically effectiveamount is well within the capability of those skilled in the art.

In certain embodiments, a pharmaceutical composition comprising one ormore compounds of the present embodiments is formulated as a prodrug. Incertain embodiments, prodrugs are useful because they are easier toadminister than the corresponding active form. For example, in certaininstances, a prodrug may be more bioavailable (e.g., through oraladministration) than is the corresponding active form. In certaininstances, a prodrug may have improved solubility compared to thecorresponding active form. In certain embodiments, a prodrug is anester. In certain embodiments, such prodrugs are less water soluble thanthe corresponding active form. In certain instances, such prodrugspossess superior transmittal across cell membranes, where watersolubility is detrimental to mobility. In certain embodiments, the esterin such prodrugs is metabolically hydrolyzed to carboxylic acid. Incertain instances the carboxylic acid containing compound is thecorresponding active form. In certain embodiments, a prodrug comprises ashort peptide (polyaminoacid) bound to an acid group. In certain of suchembodiments, the peptide is metabolized to form the corresponding activeform.

In certain embodiments, a pharmaceutical composition comprising one ormore compounds of the present embodiments is useful for treating acondition or disorder in a mammal, such as a human. Suitableadministration routes include, but are not limited to, oral, rectal,transmucosal, intestinal, enteral, topical, suppository, throughinhalation, intrathecal, intraventricular, intraperitoneal, intranasal,intraocular and parenteral (e.g., intravenous, intramuscular,intramedullary, and subcutaneous). In certain embodiments,pharmaceutical intrathecals are administered to achieve local ratherthan systemic exposures. For example, pharmaceutical compositions may beinjected directly in the area of desired effect (e.g., in the renal orcardiac area).

In certain embodiments, a pharmaceutical composition comprising acompound of the present embodiments is prepared for oral administration.In certain of such embodiments, a pharmaceutical composition isformulated by combining one or more compounds of the present embodimentswith one or more pharmaceutically acceptable carriers. Certain of suchcarriers enable compounds of the present embodiments to be formulated astablets, pills, dragees, capsules, liquids, gels, syrups, slurries,suspensions and the like, for oral ingestion by a patient. In certainembodiments, pharmaceutical compositions for oral use are obtained bymixing one or more compounds of the present embodiments and one or moresolid excipient. Suitable excipients include, but are not limited to,fillers, such as sugars, including lactose, sucrose, mannitol, orsorbitol; cellulose preparations such as, for example, maize starch,wheat starch, rice starch, potato starch, gelatin, gum tragacanth,methyl cellulose, hydroxypropylmethyl-cellulose, sodiumcarboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). In certainembodiments, such a mixture is optionally ground and auxiliaries areoptionally added. In certain embodiments, pharmaceutical compositionsare formed to obtain tablets or dragee cores. In certain embodiments,disintegrating agents (e.g., cross-linked polyvinyl pyrrolidone, agar,or alginic acid or a salt thereof, such as sodium alginate) are added.

In certain embodiments, dragee cores are provided with coatings. Incertain of such embodiments, concentrated sugar solutions may be used,which may optionally contain gum arabic, talc, polyvinyl pyrrolidone,carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquersolutions, and suitable organic solvents or solvent mixtures. Dyestuffsor pigments may be added to tablets or dragee coatings.

In certain embodiments, pharmaceutical compositions for oraladministration are push-fit capsules made of gelatin. Certain of suchpush-fit capsules comprise one or more compounds of the presentembodiments in admixture with one or more filler such as lactose,binders such as starches, and/or lubricants such as talc or magnesiumstearate and, optionally, stabilizers. In certain embodiments,pharmaceutical compositions for oral administration are soft, sealedcapsules made of gelatin and a plasticizer, such as glycerol orsorbitol. In certain soft capsules, one or more compounds of the presentembodiments are be dissolved or suspended in suitable liquids, such asfatty oils, liquid paraffin, or liquid polyethylene glycols. Inaddition, stabilizers may be added.

In certain embodiments, a pharmaceutical composition is prepared foradministration by injection (e.g., intravenous, subcutaneous,intramuscular, etc.). In certain of such embodiments, a pharmaceuticalcomposition comprises a carrier and is formulated in aqueous solution,such as water or physiologically compatible buffers such as Hanks'ssolution, Ringer's solution, or physiological saline buffer. In certainembodiments, other ingredients are included (e.g., ingredients that aidin solubility or serve as preservatives). In certain embodiments,injectable suspensions are prepared using appropriate liquid carriers,suspending agents and the like. Certain pharmaceutical compositions forinjection are presented in unit dosage form, e.g., in ampoules or inmulti-dose containers. Certain pharmaceutical compositions for injectionare suspensions, solutions or emulsions in oily or aqueous vehicles, andmay contain formulatory agents such as suspending, stabilizing and/ordispersing agents. Certain solvents suitable for use in pharmaceuticalcompositions for injection include, but are not limited to, lipophilicsolvents and fatty oils, such as sesame oil, synthetic fatty acidesters, such as ethyl oleate or triglycerides, and liposomes. Aqueousinjection suspensions may contain substances that increase the viscosityof the suspension, such as sodium carboxymethyl cellulose, sorbitol, ordextran. Optionally, such suspensions may also contain suitablestabilizers or agents that increase the solubility of the compounds toallow for the preparation of highly concentrated solutions.

In certain embodiments, a pharmaceutical composition is prepared forrectal administration, such as a suppositories or retention enema.Certain of such pharmaceutical compositions comprise known ingredients,such as cocoa butter and/or other glycerides.

In certain embodiments, a pharmaceutical composition is prepared fortopical administration. Certain of such pharmaceutical compositionscomprise bland moisturizing bases, such as ointments or creams.Exemplary suitable ointment bases include, but are not limited to,petrolatum, petrolatum plus volatile silicones, lanolin and water in oilemulsions such as Eucerin™, available from Beiersdorf (Cincinnati,Ohio). Exemplary suitable cream bases include, but are not limited to,Nivea™ Cream, available from Beiersdorf (Cincinnati, Ohio), cold cream(USP), Purpose Cream™, available from Johnson & Johnson (New Brunswick,New Jersey), hydrophilic ointment (USP) and Lubriderm™, available fromPfizer (Morris Plains, New Jersey).

In certain embodiments, the formulation, route of administration anddosage for a pharmaceutical composition of the present embodiments canbe chosen in view of a particular patient's condition. In certainembodiments, a pharmaceutical composition is administered as a singledose. In certain embodiments, a pharmaceutical composition isadministered as a series of two or more doses administered over one ormore days.

In certain embodiments, a pharmaceutical composition of the presentembodiments is administered for a period of continuous therapy. Forexample, a pharmaceutical composition of the present embodiments may beadministered over a period of days, weeks, months, or years.

In certain embodiments, a pharmaceutical composition may be presented ina pack or dispenser device which may contain one or more unit dosageforms containing the active ingredient. The pack may for examplecomprise metal or plastic foil, such as a blister pack. The pack ordispenser device may be accompanied by instructions for administration.The pack or dispenser may also be accompanied with a notice associatedwith the container in form prescribed by a governmental agencyregulating the manufacture, use, or sale of pharmaceuticals, whichnotice is reflective of approval by the agency of the form of the drugfor human or veterinary administration. Such notice, for example, may bethe labeling approved by the U.S. Food and Drug Administration forprescription drugs, or the approved product insert. Compositionscomprising a compound of the present embodiments formulated in acompatible pharmaceutical carrier may also be prepared, placed in anappropriate container, and labeled for treatment of an indicatedcondition.

In certain embodiments, a pharmaceutical composition is in powder formfor constitution with a suitable vehicle, e.g., sterile pyrogen-freewater, before use.

The compounds are administered at a therapeutically effective dosage,e.g., a dosage sufficient to provide treatment for the disease statespreviously described. While human dosage levels have yet to be optimizedfor the compounds of the preferred embodiments, generally, a daily dosefor most of the compounds described herein is from about 0.25 mg/kg toabout 120 mg/kg or more of body weight, from about 0.5 mg/kg or less toabout 70 mg/kg, from about 1.0 mg/kg to about 50 mg/kg of body weight,or from about 1.5 mg/kg to about 10 mg/kg of body weight. Thus, foradministration to a 70 kg person, the dosage range would be from about17 mg per day to about 8000 mg per day, from about 35 mg per day or lessto about 7000 mg per day or more, from about 70 mg per day to about 6000mg per day, from about 100 mg per day to about 5000 mg per day, or fromabout 200 mg to about 3000 mg per day. The amount of active compoundadministered will, of course, be dependent on the subject and diseasestate being treated, the severity of the affliction, the manner andschedule of administration and the judgment of the prescribingphysician.

Administration of the compounds disclosed herein or the pharmaceuticallyacceptable salts thereof can be via any of the accepted modes ofadministration for agents that serve similar utilities including, butnot limited to, orally, subcutaneously, intravenously, intranasally,topically, transdermally, intraperitoneally, intramuscularly,intrapulmonarilly, vaginally, rectally, or intraocularly. Oral andparenteral administrations are customary in treating the indicationsthat are the subject of the preferred embodiments.

Certain Therapeutic Methods

Some compounds and compositions provided herein, such as compoundsand/or compositions comprising Formula I are useful for the treatment ofa variety of diseases and disorders malignant or benign hematopoieticdisorders. Examples of leukemia include acute lymphocytic leukemia(ALL), chronic lymphocytic leukemia (CLL), acute myelogenous leukemia,chronic myelogenous leukemia (CML), chronic idiopathic myelofibrosis,chronic neutrophilic leukemia (CNL), and acute monocytic leukemia.

In some embodiments, the compounds and compositions provided herein canbe administered in combination with one or more additional anticanceragent(s) or treatment. Examples of other anticancer agents or treatmentinclude HDAC inhibitors, chemotherapy, immunotherapy, VEGFR modulators,bone marrow transplant, and stem cell transplant.

EXAMPLES

The following examples, including experiments and results achieved, areprovided for illustrative purposes only and are not to be construed aslimiting the present invention. Where chemical structures depict atomshaving an unfilled valency, it is to be understood that the valency issatisfied with one or more hydrogen atoms.

Example 16-(4-Pyridinyl)-2-(4-(1-pyrrolidinylmethyl)-2-pyridinyl)imidazo[1,2-a]pyrazine(Compound 101)

Compound 101 was prepared according to the general procedure describedin Scheme I from 5-bromopyrazin-2-amine as follows.

Preparation of 2-(5-bromo-2-(tosylimino)pyrazin-1(2H)-yl)acetamide(Compound 2A)

A mixture of 5-bromopyrazin-2-amine (2.8 g, 16 mmol) and TsCl (3.7 g, 19mmol) in pyridine (50 mL) was stirred at 90° C. for 5 h. The residue wasconcentrated under reduce pressure. The residue was diluted with 100 mLof water and the solid formed was collected, washed with water, anddried under vacuum to give the N-tosyl 5-bromopyrazin-2-amine (4.5 g,85%). A mixture of the N-tosyl intermediate (4.5 g, 14 mmol),bromoacetamide (2.1 g, 15 mmol), and DIEA (1.9 g, 15 mmol) in DMF (60mL) was stirred at room temperature for 48 h. The residue was pouredinto 300 mL water and the resulting solid was filtered and dried undervacuum to give Compound 2A (4.7 g, 87% yield).

Preparation of 6-(pyridin-4-yl)imidazo[1,2-a]pyrazin-2-amine (Compound4A)

To a suspension of Compound 2A (4.7 g, 12 mmol) in DCM (60 mL) was addedTFAA (10 mL) and the resulting mixture was stirred at room temperaturefor 3 hours. The mixture was concentrated and diluted with 100 mL ofaqueous NaHCO₃. The crude mixture was purified by column chromatography(PE/EA=5/1) to give Compound 3A as white solid (1.3 g, 35% yield). Amixture of Compound 3A (463 mg, 1.5 mmol), boronic acid (246 mg, 2mmol), PdCl₂(PPh₃)₂ (210 mg, 0.3 mmol), and K₂CO₃ (1.2 g, 4.5 mmol) indioxane/water (5/1, 12 mL) was stirred at 100° C. in a microwave reactorfor 2 hours. The mixture was concentrated and treated with K₂CO₃ (1.4 g,10 mmol) in dioxane/water (1/1, 20 mL) at 100° C. for 2 hours. Afterconcentrated, the residue was stirred with 20 mL MeOH to form a crudesolid that was purified by prep-HPLC (basic condition) to give Compound4A (260 mg, 82%).

Preparation of6-(4-pyridinyl)-2-(4-(1-pyrrolidinylmethyl)-2-pyridinyl)imidazo[1,2-a]pyrazine(Compound 101)

A mixture of Compound 4A (100 mg, 0.47 mmol) and Compound 5A (100 mg,0.51 mmol), BINAP (20 mg, 0.032 mmol), Pd₂(dba)₃ (20 mg, 0.022 mmol),Cs₂CO₃ (307 mg, 0.95 mmol) in dioxane (10 mL) was stirred at 100° C. for12 hours. The reaction mixture was concentrated and purified byprep-HPLC to give the desired compound as yellow solid (35 mg, 18%yield). ¹H-NMR (400 MHz, MeOD) 9.66 (d, J=1.2, 1H), 9.26 (s, 1H), 8.93(d, J=6.4, 1H), 8.78 (d, J=6.8, 1H), 8.44 (d, J=6.4, 1H), 7.67 (s, 1H),7.44 (dd, J=6.4 and 1.2, 1H), 4.62 (s, 2H), 3.80-3.55 (m, 4H), and2.30-2.10 (m, 4H).

Example 26-(4-Pyridinyl)-2-(4-(1-pyrrolidinylmethyl)-2-pyridinyl)imidazo[1,2-a]pyridazine(Compound 102)

Preparation of 2-(5-bromo-2-(tosylimino)pyrazin-1(2H)-yl)acetamide(Compound 2B)

A mixture of Compound 1B (6.8 g, 52 mmol) and TsCl (11 g, 57 mmol) inpyridine (60 mL) was stirred at 90° C. for 4 h. The mixture wasconcentrated under reduce pressure and diluted with 50 mL water to formthe crude solid. The solid was washed with water and dried under vacuumto give the N-tosyl intermediate (10 g, 67%). A mixture of the N-tosylintermediate (4.0 g, 14 mmol), bromoacetamide (2.2 g, 16 mmol), and DIEA(2.0 g, 16 mmol) in DMF (30 mL) was stirred at room temperature for 8hours. The mixture was poured into 200 mL of ice water and stirred for0.5 hour. The resulting solid was filtered and dried under vacuum togive Compound 2B (4.3 g, 89% yield).

Preparation of 6-(pyridin-4-yl)imidazo[1,2-a]pyrazin-2-amine (Compound4B)

To a suspension of Compound 2B (2.0 g, 5.9 mmol) in DCM (30 mL) wasadded TFAA (10 mL). The mixture was stirred at room temperature for 3hours. The reaction mixture was concentrated and diluted with 50 mL ofaqueous NaHCO₃ to gave the crude solid, and further purification bycolumn chromatography (PE/EA=5/1) afforded Compound 3B as white solid(1.3 g, 85% yield). A mixture of Compound 3B (529 mg, 2.0 mmol),4-pyridineboronic acid (369 mg, 3.0 mmol), PdCl₂(PPh₃)₂ (280 mg, 0.4mmol), and K₂CO₃ (552 mg, 4.0 mmol) in dioxane/water (4/1, 15 mL) wasstirred at 100° C. in a microwave reactor for 1.5 hours. The reactionmixture was concentrated and purified by column (PE/EA=1/1 thenDCM/MeOH=20/1) to give N-trifluoroacetyl protected Compound 4B as ayellow solid (250 mg, 40% yield). Deprotection reaction with K₂CO₃ (817mg, 5.9 mmol) in dioxane/MeOH/H₂O (1/1/1, 30 mL) at 100° C. for 1 hourto give Compound 4B as a solid (80 mg, 46% yield).

Preparation of6-(4-Pyridinyl)-2-(4-(1-pyrrolidinylmethyl)-2-pyridinyl)imidazo[1,2-a]pyridazine(Compound 102)

A mixture of Compound 4B (80 mg, 0.38 mmol), Compound 5A (80 mg, 0.41mmol), BINAP (15 mg, 0.024 mmol), Pd₂(dba)₃ (15 mg, 0.016 mmol), Cs₂CO₃(246 mg, 0.76 mmol) in dioxane (5 mL) was stirred at 100° C. for 12 h.The reaction mixture was concentrated and purified by prep-HPLC to giveCompound 102 as yellow solid (30 mg, 21% yield). ¹H-NMR (400 MHz,DMSO-d6) 11.85 (bs, 1H), 11.11 (s, 1H), 9.26 (s, 1H), 9.04 (d, J=4.4,2H), 8.63 (t, J=6.4, 2H), 8.38 (d, J=5.6, 1H), 8.21 (d, J=9.6, 1H), 8.12(d, J=9.2, 1H), 7.41 (d, J=5.6, 1H), 7.33 (s, 1H), 4.40 (d, J=5.6, 2H),3.40 (bs, 2H), 3.06 (bs, 2H), and 2.02-1.91 (m, 4H).

Example 3

The following inhibitory assay is useful for evaluating test compoundsfor inhibition of Flt3 kinase activity. The assay is performed usingtraditional radioisotope filtration binding.

A base reaction buffer is prepared consisting of 20 mM Hepes (pH 7.5),10 mM MgCl₂, 1 mM EGTA, 0.02% Brij35, 0.02 mg/ml BSA, 0.1 mM Na₃PO₄, 2mM DTT, 1% DMSO. The peptide substrate abltide [EAIYAAPFAKKK] is addedto the base reaction buffer to yield a final concentration of 5 μM.Additional cofactors (1.5 mM CaCl₂, 16 ug/ml Calmodulin, and 2 mM MnCl₂)are added to the buffer/substrate solution. Recombinant human FLT3(baculovirus expression system using a C-terminal His6-tag) is added tothe solution and gently mixed. Test compounds are dissolved in DMSO andadded to the buffer/kinase solution to yield a final concentration of 5μM. Compounds were tested in a 10-dose IC50 in duplicate with 3-foldserial dilution starting at 1 μM to yield a full dose response curve.Staurosporine was used as positive control with a 10-dose IC50 with3-fold serial dilution starting at 20 μM to yield a dose response curve.The reaction is initiated by the addition of ³³P-ATP (specific activity500 Ci/μl) into the reaction mixture to a final concentration of 10 μM.The kinase reaction was incubated for 120 minutes at room temperature.The reactions are spotted onto P81 ion exchange paper (Whatman#3698-915) and the filter papers are extensively washed in 0.75%Phosphoric acid and beta emissions are measured. Flt3 inhibition IC50values of the compounds are in the table below.

Number Flt3 inhibition IC₅₀ (nM) Compound 101 0.11 Compound 102 0.25Staurosporine <1.0

All references cited herein, including but not limited to published andunpublished applications, patents, and literature references, areincorporated herein by reference in their entirety and are hereby made apart of this specification. To the extent publications and patents orpatent applications incorporated by reference contradict the disclosurecontained in the specification, the specification is intended tosupersede and/or take precedence over any such contradictory material.

All numbers expressing quantities of ingredients, reaction conditions,and so forth used in the specification are to be understood as beingmodified in all instances by the term “about.” Accordingly, unlessindicated to the contrary, the numerical parameters set forth herein areapproximations that may vary depending upon the desired propertiessought to be obtained. At the very least, and not as an attempt to limitthe application of the doctrine of equivalents to the scope of anyclaims in any application claiming priority to the present application,each numerical parameter should be construed in light of the number ofsignificant digits and ordinary rounding approaches.

The above description discloses several methods and materials of thepresent invention. This invention is susceptible to modifications in themethods and materials, as well as alterations in the fabrication methodsand equipment. Such modifications will become apparent to those skilledin the art from a consideration of this disclosure or practice of theinvention disclosed herein. Consequently, it is not intended that thisinvention be limited to the specific embodiments disclosed herein, butthat it cover all modifications and alternatives coming within the truescope and spirit of the invention.

What is claimed is:
 1. A compound of Formula (III):

or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof,wherein R¹ is selected from the group consisting of an optionallysubstituted (5 to 7 membered heterocyclyl)alkyl, an optionallysubstituted aralkyl; and an optionally substituted (5 or 6 memberedheteroaryl)alkyl; each of R², R³, and R^(4a) is independently selectedfrom the group consisting of hydrogen, halogen, C₁₋₆ alkyl, OH, and C₁₋₆alkoxy; each of R^(5a) and R^(5b) is independently selected from thegroup consisting of hydrogen, halogen, —OR⁶, —CN, —NR⁷R⁸, —CH₂OR⁶, anoptionally substituted aryl, an optionally substituted 5 to 10 memberedheteroaryl, an optionally substituted 5-10 membered heterocyclyl, anoptionally substituted C₃₋₇ carbocyclyl, an optionally substituted C₁₋₆alkyl, an optionally substituted C₁₋₆ haloalkyl, an optionallysubstituted C₁₋₆ heteroalkyl, —C(═O)R⁶, —C(═O)OR⁶, —C(═O)NR⁷R⁸,—NHC(═O)R⁶, —SO₂R⁶, and —SO₂NR⁷R⁸; each R⁶ is independently hydrogen, anoptionally substituted C₁₋₁₀ alkyl, an optionally substituted C₁₋₁₀haloalkyl, or an optionally substituted C₁₋₆ heteroalkyl; and each R⁷and R⁸ is independently selected from hydrogen; an optionallysubstituted C₁₋₁₀ alkyl; an optionally substituted C₁₋₁₀ haloalkyl; oran optionally substituted C₁₋₆ heteroalkyl; or R⁷ and R⁸ are joinedtogether with the nitrogen atom to which they are attached to form anoptionally substituted C₃₋₇ cycloalkyl or 3 to 7 membered heterocyclylring.
 2. The compound of claim 1, wherein each of R^(4a) and R^(5a) ishydrogen.
 3. The compound of claim 1, wherein R¹ is an optionallysubstituted (5 to 7 membered heterocyclyl)alkyl.
 4. The compound ofclaim 3, wherein R¹ is an optionally substituted (5 memberedheterocyclyl)alkyl.
 5. The compound of claim 4, wherein R¹ ispyrrolidyl-CH₂—.
 6. The compound of claim 3, wherein R¹ is an optionallysubstituted (6 membered heterocyclyl)alkyl.
 7. The compound of claim 6,wherein R¹ is piperidinyl-CH₂— or morpholine-CH₂—.
 8. The compound ofclaim 1, wherein R² is hydrogen.
 9. The compound of claim 1, wherein R³is hydrogen.
 10. The compound of claim 1, wherein R^(5b) is anoptionally substituted 5 to 10 membered heteroaryl.
 11. The compound ofclaim 10, wherein R^(5b) is an optionally substituted 6 memberedheteroaryl.
 12. The compound of claim 11, wherein R^(5b) is pyridyl,pyrazinyl, pyridazinyl, or pyrimidyl.
 13. The compound of claim 10,wherein R^(5b) is an optionally substituted 5 membered heteroaryl. 14.The compound of claim 13, wherein R^(5b) is pyrazolyl.
 15. The compoundclaim 1, having the structure

or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.16. A pharmaceutical composition comprising an effective amount of acompound of claim 1, or a pharmaceutically acceptable salt, ester,amide, or prodrug thereof, and one or more pharmaceutically acceptablecarriers, diluents, excipients, or combinations thereof.
 17. Thecompound of claim 2, wherein R¹ is an optionally substituted (5 to 7membered heterocyclyl)alkyl.
 18. The compound of claim 17, wherein R¹ isan optionally substituted (5 membered heterocyclyl)alkyl.
 19. Thecompound of claim 18, wherein R¹ is pyrrolidyl-CH₂—.